The β-amino-α-hydroxy carboxamide derivative (1) obtained according to the production process of the present invention is important intermediates for the production of drugs such as antiviral agents (see Patent Document 1). These compounds are used as, for example, intermediates for HIV protease inhibitors and hepatitis C remedies.
Conventionally, as a process for producing the β-amino-α-hydroxy carboxamide derivative (1), for example, there have been reported;
(i) a process for production of (3S)-3-amino-2-hydroxy-4-phenylbutanoic acid cyclohexylmethylamide hydrochloride by dissolving (3S)-3-N-(tert-butoxycarbonyl)amino-2-hydroxy-4-phenylbutanoic acid in DMF, reacting the solution with cyclohexylmethylamine, N-hydroxy-norbornene-2,3-dicarboxylimide (HOBN) and 1-ethyl-3-(3-N,N-dimethylaminopropyl)carbodiimide (EDC) hydrochloride added thereto for conversion to (3S)-3-N-(tert-butoxycarbonyl)amino-2-hydroxy-4-phenylbutanoic acid cyclohexylmethylamide, and thereafter adding 4 N-hydrochloric acid/dioxane thereto for removal of Boc, then purifying the deprotected compound by column chromatography (chloroform/methanol) in the presence of ether, and again adding 4 N-hydrochloric acid/dioxane thereto (see Patent Document 2);
(ii) a process for production of (3S)-3-amino-2-hydroxyhexanoic acid cyclopropylamide by reacting (2S)-2-N-carbamate-protected amino-2-alkyl-ethanal with cyclopropyl-isonitrile for conversion to (3S)-3-N-carbamate-protected amino-2-acyloxypropanoic acid cyclopropylamide, then deprotecting the 2-positioned hydroxyl group, and further removing Boc using 4 N-hydrochloric acid/dioxane, and thereafter evaporating away the solvent (see Patent Document 3).
However, the conventional methods have some problems for industrial scale production in that unfavorable reagents, such as DMF, chloroform and 1,4-dioxane having a problem of negative influence on the environment, diethyl ether that is an extremely highly flammable organic solvent, isonitrile derivatives having disadvantage in point of bad smell and production difficulty, are used, and large quantities of plural organic solvents are used.
In the conventional process for purification of the β-amino-α-hydroxy carboxamide derivative (1), disclosed is a process of column chromatography (eluent: chloroform/methanol) as a purification method. The process has serious problems for industrial scale production in that a large quantity of an unfavorable solvent such as chloroform is used, steps are complicated, the number and the volume of the production apparatuses are increased, and the yield is low. Further, in the conventional process, for example, disclosed is a process for obtaining (3S)-3-amino-2-hydroxyhexanoic acid cyclopropylamide hydrochloride as a crystal by evaporating the solvent from a mixture with 1,4-dioxane. However, it has been found by investigations of the present inventors that 3-amino-2-hydroxyhexanoic acid cyclopropylamide hydrochloride is solidified during the solvent evaporation in the process, and as a result, stirring becomes impossible. It has been found that the crystal is extremely difficult to be filtered. The both of the above condition result is that the operation could no more be continued or the operation time is prolonged, and therefore, it could not be said that the process may be suitable for industrial scale.
As mentioned above, the β-amino-α-hydroxy amide derivative (1) is intermediate for HIV protease inhibitors and hepatitis C remedies to be taken in a large dose, and therefore development of a practicable process for the mass-production thereof has a particularly important meaning.
Patent Document 1: WO02/018639
Patent Document 2: JP-A 5-170722
Patent Document 3: WO05/058821